Genetic Risk Factors in Normal Pressure Hydrocephalus: What We Know and What Is Next

Area of Science:

• Neurogenetics
• Human Genetics
• Neurology

Background:

• Normal pressure hydrocephalus (NPH) is a neurological condition with an evolving understanding of its genetic underpinnings.
• Familial cases and genetic associations suggest a hereditary component to NPH.
• Previous research has explored genetic links, but a comprehensive review is needed.

Purpose of the Study:

• To systematically review and synthesize current knowledge on genetic factors contributing to normal pressure hydrocephalus (NPH) risk.
• To identify specific genetic variants, familial patterns, and associations with other neurogenetic disorders in NPH.
• To explore the role of transcriptomics in understanding NPH pathogenesis.

Main Methods:

• Systematic literature search of Ovid Embase, Ovid Medline, Web of Science, and Cochrane Central up to October 14, 2024.
• Inclusion of human studies reporting familial NPH, genetic variants, associations with other neurogenetic disorders, and transcriptomics.
• Exclusion of secondary, obstructive, and congenital hydrocephalus; narrative reporting of findings.

Main Results:

• 56 studies met inclusion criteria, primarily from European populations, identifying over 30 familial NPH cases.
• 10%-16% of NPH patients had relatives with NPH symptoms, indicating familial aggregation.
• Risk variants near genes (e.g., CFAP43, SFMBT1, CWH43) involved in barrier functions and cilia, plus associations with C9orf72 expansions and other neurodegenerative diseases, were identified.

Conclusions:

• Genetic factors play a significant role in normal pressure hydrocephalus (NPH) risk, influencing barrier function and cilia.
• Further research requires big data generation, diverse genetic variant identification, and integration of clinical and environmental data.
• Understanding genetic contributions is crucial for advancing NPH research and potential therapeutic strategies.